The present invention is directed to the synthesis of xcex3-hydroxy-4-[[2-oxazolyl]alkyl]-xcex1-[(cyclo)alkyl- or aryl- or heteroaryl-substituted methyl]-2-[[(un)substituted alkyl]aminocarbonyl]-1-piperazinepentanamides which are HIV protease inhibitors. The present invention also includes the preparation of intermediates useful in the synthesis of the piperazinepentanamide HIV protease inhibitors.
The HIV retrovirus is the causative agent for AIDS. The HIV-1 retrovirus primarily uses the CD4 receptor (a 58 kDa transmembrane protein) to gain entry into cells, through high-affinity interactions between the viral envelope glycoprotein (gp 120) and a specific region of the CD4 molecule found in T-lymphocytes and CD4 (+) T-helper cells (Lasky L. A. et al., Cell 1987, 50: 975-985). HIV infection is characterized by an asymptomatic period immediately following infection that is devoid of clinical manifestations in the patient. Progressive HIV-induced destruction of the immune system then leads to increased susceptibility to opportunistic infections, which eventually produces a syndrome called AIDS-related complex (ARC) characterized by symptoms such as persistent generalized lymphadenopathy, fever, and weight loss, followed itself by full blown AIDS.
As in the case of several other retroviruses, HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al., J. Virol. 1985, 53: 899). These gene products include polxe2x80x94which encodes the virion RNA-dependent DNA polymerase (reverse transcriptase), an endonuclease, and HIV proteasexe2x80x94and gagxe2x80x94which encodes the core-proteins of the virion. (H. Toh et al., EMBO J. 1985, 4: 1267; L. H. Pearl et al., Nature 1987, 329-351; M. D. Power et al., Science 1986, 231: 1567).
A number of synthetic anti-viral agents targeted to various stages in the replication cycle of HIV have been disclosed. These agents include inhibitors of HIV cellular fusion (Turpin et al., Expert Opinion on Therapeutic Patents 2000, 10: 1899-1909), reverse transcriptase inhibitors (e.g., didanosine, zidovudine (AZT), and efavirenz), integrase inhibitors (Neamati, Expert Opinion on Investigational Drugs 2000, 10: 281-296), and protease inhibitors (e.g., indinavir, ritonavir, and saquinavir). Protease inhibitors inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus-encoded proteases which are essential for replication (Kohl, N. E. et al., Proc. Natl. Acad. Sci. USA 1988, 85: 4686).
A substantial and persistent problem in the treatment of AIDS has been the ability of the HIV virus to develop resistance to the therapeutic agents employed to treat the disease. Resistance to HIV-1 protease inhibitors has been associated with 25 or more amino acid substitutions in both the protease and the cleavage sites. Many of these viral variants are resistant to all of the HIV protease inhibitors currently in clinical use. See Condra et al., Drug Resistance Updates 1998, 1: 1-7; Condra et al., Nature 1995, 374: 569-571; Condra et al., J. Virol. 1996, 70:8270-8276; Patrick et al., Antiviral Ther. 1996, Suppl. 1: 17-18; and Tisdale et al., Antimicrob. Agents Chemother. 1995, 39: 1704-1710.
Certain xcex3-hydroxy-4-[[2-oxazolyl]alkyl]-xcex1-[substituted methyl]-2-[[fluoroalkyl)amino]carbonyl]-1-piperazinepentanamides are HIV protease inhibitors which are much more potent against HIV viral mutants than protease inhibitors presently in clinical use. The synthesis of these compounds is a complicated, multi-step process having a relatively low overall yield. The synthesis of these compounds can be represented by Scheme A as follows, wherein A10 represents the desired piperazinepentaneamide HIV protease inhibitor: 
A*=absent, CH2, or O;
R1*=aryl or heteroaryl, wherein aryl is optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, fluoroalkyl, alkoxy, fluoroalkoxy, S-alkyl, amino, or heteroaryl; and heteroaryl is optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, fluoroalkyl, alkoxy, fluoroalkoxy, S-alkyl, amino, aryl, or heteroaryl.
R2*, R3*=H or alkyl; or
R2 * and R3 * together with the carbon to which they are attached form cycloalkyl;
R6*=monofluoroalkyl or polyfluoroalkyl;
R7*=alkyl, cycloalkyl, aryl or heteroaryl, wherein aryl is optionally substituted with one or more of halogen, OH, alkyl, alkenyl, alkynyl, fluoroalkyl, alkoxy, or heteroaryl; and heteroaryl is optionally substituted with one or more of halogen, OH, alkyl, alkenyl, alkynyl, fluoroalkyl, alkoxy, or aryl;
R8*, R9*=H, OH, alkyl, fluoroalkyl, or alkoxy; or
R8* and R9* together with the carbons to which they are attached form a fused benzene ring.
WO 01/38332 presents a specific example of Scheme A in Example 85, which describes the preparation of (xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[5-(5-methoxy-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide (hereinafter alternatively referred to as Compound 26).
The preparation of the ketoamines of formula R1*xe2x80x94C(xe2x95x90O)CH2NH2 employed in Scheme A to make Compound A6 can be represented by Scheme B as follows: 
WO 01/38332 contains a specific example of Scheme B in Example 85, which describes the preparation of 3-aminomethylcarbonyl-5-methoxypyridine in Steps B and C.
There is a need for improvements in one or more steps of Scheme A and Scheme B in order to prepare this class of piperazinepentaneamide HIV protease inhibitors more efficiently and more conveniently.
The present invention provides for improvements in the process for preparing xcex3-hydroxy-4-[[2-oxazolyl]alkyl]-xcex1-[(cyclo)alkyl- or aryl- or heteroaryl-substituted methyl]-2-[[(un)substituted alkyl]aminocarbonyl]-1-piperazinepentanamides. The present invention includes an improved process for making a 4-[[2-oxazolyl]alkyl]-2-[[(un)substituted alkyl]aminocarbonyl]piperazine by treating a ketoamide precursor with fuming sulfuric acid in the presence of polyphosphoric acid. The present invention also includes a process for enhancing the optical purity of 4-[[2-oxazolyl]alkyl]-2-[[(un)substituted alkyl]aminocarbonyl]-piperazines via the formation 2-naphthalenesulfonic acid crystal salts thereof. The present invention further includes a method for purifying 2-naphthalenesulfonic acid.
The foregoing embodiments as well as other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.
The present invention includes a process for preparing a piperazine of Formula (II): 
which comprises:
(A) treating a ketoamide of Formula (I): 
xe2x80x83with fuming sulfuric acid in the presence of polyphosphoric acid to obtain the piperazine II; wherein
stereocenter a is either in the R configuration or in the S configuration;
G is a nitrogen-protecting group;
R1 is: 
xe2x80x83heterocycle, or substituted heterocycle;
wherein each Q is independently hydrogen, cyano, C1-C4 alkyl, or xe2x80x94Oxe2x80x94C1-C4 alkyl;
heterocycle in R1 is: 
substituted heterocycle in R1 is a heterocycle as defined above with one or more substituents (e.g., from 1 to 4 substituents, or from 1 to 3 substituents; or is di-substituted; or is mono-substituted) independently selected from cyano, C1-C4 alkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl, Sxe2x80x94(C1-C4 alkyl), NRaRb, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl, isoxazolyl, and isothiazolyl;
R2 and R3 are each independently hydrogen, C1-C6 alkyl, or aryl, wherein the alkyl group is optionally substituted with one or more substituents (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3 substituents; or is di-substituted; or is mono-substituted) each of which is independently halogen, xe2x80x94Oxe2x80x94C1-C6 alkyl, or xe2x80x94Oxe2x80x94C1-C6 haloalkyl; and wherein the aryl group is optionally substituted with one or more substituents each of which is independently halogen, xe2x80x94C1-C6 alkyl, xe2x80x94C1-C6 haloalkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, or xe2x80x94Oxe2x80x94C1-C6 haloalkyl; or
R2 and R3 together with the carbon to which they are attached form C3-C8 cycloalkyl which is optionally substituted with one or more substituents (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3 substituents; or is di-substituted; or is mono-substituted) each of which is independently halogen, xe2x80x94C1-C6 alkyl, xe2x80x94C1-C6 haloalkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 haloalkyl, or xe2x80x94C1-C6 alkyl substituted with xe2x80x94Oxe2x80x94C1-C6 alkyl;
R6 is xe2x80x94H or C1-C6 alkyl optionally substituted with one or more substituents (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3 substituents; or is di-substituted; or is mono-substituted) each of which is independently
(1) halogen,
(2) xe2x80x94Oxe2x80x94C1-C6 alkyl,
(3) xe2x80x94Oxe2x80x94C1-C6 haloalkyl,
(4) xe2x80x94C1-C6 alkyl substituted with xe2x80x94C1-C6 alkyl,
(5) xe2x80x94N(Rc)2,
(6) xe2x80x94CO2Rc,
(7) xe2x80x94N(Rc)(SO2Rc),
(8) xe2x80x94C(xe2x95x90O)Rc, or
(9) xe2x80x94C(xe2x95x90O)xe2x80x94N(Rc)2;
Ra and Rb are each independently xe2x80x94H or xe2x80x94C1-C4 alkyl; or alternatively Ra and Rb together with the nitrogen to which they are attached form C1-C6 azacycloalkyl;
each Rc is independently xe2x80x94H or xe2x80x94C1-C4 alkyl; and
t is an integer equal to zero, 1 or 2.
In the definition of stereocenter a in the above process, it is to be understood that stereocenter a is either wholly or substantially in the R or the S configuration. The term xe2x80x9csubstantiallyxe2x80x9d means that the ketoamide I reactant generally has at least about a 20% enantiomeric excess (ee) of the desired configuration over the other, typically has at least about a 40% ee, and more typically has at least an 80% ee of one configuration over the other at stereocenter a. Ketoamide I often has a 90% to 99% ee, or even has 100% ee, of one configuration over the other. In one embodiment of the process, ketoamide I is in the S configuration at stereocenter a; i.e., ketoamide I is wholly or substantially in the S configuration.
In an embodiment of the process of the invention, R1 is as originally defined, except that Ra and Rb are each independently xe2x80x94H or xe2x80x94C1-C4 alkyl. In other embodiments, R1 is as originally defined, except that Ra and Rb are both xe2x80x94H; or Ra and Rb are each a xe2x80x94C1-C4 alkyl; or Ra and Rb are each independently xe2x80x94H, methyl, or ethyl; or Ra and Rb together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, or piperidinyl.
In another embodiment of the process of the invention, R1 in ketoamide I and piperazine II is 
heterocycle, or substituted heterocycle;
wherein each Q is independently hydrogen, cyano, C1-C4 alkyl, or xe2x80x94Oxe2x80x94C1-C4 alkyl; heterocycle is 
substituted heterocycle is heterocycle as defined above having from 1 to 3 substituents independently selected from C1-C4 alkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl, xe2x80x94Sxe2x80x94CH3, xe2x80x94N(CH3)2, thiazolyl, and oxazolyl; and
t is an integer equal to zero, 1 or 2.
In another embodiment, R1 is: 
heterocycle, or substituted heterocycle;
wherein each Q is independently hydrogen, C1-C4 alkyl, or xe2x80x94Oxe2x80x94C1-C4 alkyl;
heterocycle is 
substituted heterocycle is heterocycle as defined above having from 1 to 3 substituents independently selected from C1-C4 alkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl, xe2x80x94Sxe2x80x94CH3, and xe2x80x94N(CH3)2; and
t is an integer equal to zero, 1 or 2.
In still another embodiment of the process, R1 is pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from optionally substituted with C1-C4 alkyl or xe2x80x94Oxe2x80x94C1-C4 alkyl. In an aspect of this embodiment, R1 is pyridyl which is unsubstituted or substituted with methyl or methoxy. In another aspect of this embodiment, R1 is: 
In an embodiment of the process of the invention, R2 and R3 in ketoamide I and piperazine II are each independently hydrogen or C1-C4 alkyl; or R2 and R3 together with the carbon to which they are attached form C1-C6 cycloalkyl. In another embodiment, R2 and R3 are either both xe2x80x94H or both methyl.
In an embodiment of the process of the invention, R6 is as originally defined, except that each Rc is xe2x80x94H. In other embodiments, R6 is as originally defined, except that each Rc is a xe2x80x94C1-C4 alkyl; or each Rc is independently xe2x80x94H, methyl, or ethyl; or each Rc is methyl.
In another embodiment, R6 is C1-C6 alkyl optionally substituted with one or more halogens each of which is independently fluoro, chloro, or bromo. In another embodiment, R6 is C1-C4 alkyl or C1-C4 fluoroalkyl. In still another embodiment, R6 is 
In an aspect of the preceding embodiment, R6 is 
In the process of the invention, G is a nitrogen-protecting group. The choice of the nitrogen-protecting group is not critical. G can be, for example, any of the amino nitrogen protective groups described in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1981, pp. 218-287 and in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d edition, John Wiley and Sons, 1991, pp. 309-405. Suitable G groups include: (1) (C1-C8 alkyl)oxycarbonyl, (2) allyloxycarbonyl, (3) benzyloxycarbonyl wherein benzyl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, C1-C4 alkyl or xe2x80x94Oxe2x80x94C1-C4 alkyl, (4) p-nitrobenzyloxycarbonyl, (5) phenyloxycarbonyl wherein phenyl is optionally substituted with from 1 to 3 substituents each of which is independently C1-C4 alkyl or xe2x80x94Oxe2x80x94C1-C4 alkyl, and (6) methylcarbonyl wherein the methyl is optionally substituted with from 1 to 3 substituents each of which is independently chloro or fluoro. In one embodiment, G is butyloxycarbonyl, t-amyloxycarbonyl, diisopropylmethyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, phenyloxycarbonyl, p-methoxybenzylcarbonyl, 2,4,6-trimethylbenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, or trifluoroacetyl. In an aspect of this embodiment, G is allyloxycarbonyl.
In the process of the invention, any amount of fuming sulfuric acid can be employed in Step A which results in the formation of at least some of Compound II. Of course, the maximum conversion of Compound I and maximum yield of Compound II is normally desired, and relative proportions of reactants and reagents suitable for this purpose are typically employed. In one embodiment, the fuming sulfuric acid (alternatively referred to herein as xe2x80x9coleumxe2x80x9d) is employed in an amount in the range of from about 5 to about 20 equivalents per equivalent of ketoamide I. In another embodiment, the fuming sulfuric acid is employed in an amount of from about 7 to about 11 equivalents per equivalent of ketoamide I. It is preferred to use the fuming sulfuric acid as the solvent for the reaction, although an inert co-solvent (e.g., an aliphatic hydrocarbon or an aromatic hydrocarbon) can be employed. Fuming sulfuric acid is commercially available in 15%, 20%, 30% and 60% grades. These grades can be used directly in Step A.
The oleum cyclization of ketoamide I in Step A is conducted in the presence of polyphosphoric acid. The cyclization of I with oleum alone can occur with significant racemization of stereocenter a, leading to a piperazine II product with lower optical purity. It has been found that the presence of polyphosphoric acid can significantly minimize racemization during oleum cyclization, resulting in a piperazine II with little or no degradation in optical purity. Polyphosphoric acid is suitably employed in Step A in an amount in the range of from about 0.5 to about 10 equivalents per equivalent of ketoamide I, and is typically employed in an amount of from about 2 to about 4 equivalents per equivalent of ketoamide I. In one embodiment, the ratio of equivalents of fuming sulfuric acid to equivalents of polyphosphoric acid is in the range from about 1:1 to about 30:1. In still another embodiment, the ratio of equivalents of fuming sulfuric acid to equivalents of polyphosphoric acid is in the range from about 2:1 to about 4:1. In still another embodiment, neat polyphosphoric acid is employed in Step A.
In an aspect of Step A, fuming sulfuric acid is employed in an amount in the range of from about 5 to about 20 equivalents and the polyphosphoric acid is employed in an amount in the range of from about 0.5 to about 10 equivalents per equivalent of ketoamide I. In another aspect, fuming sulfuric acid is employed in an amount in the range of from about 7 to about 11 equivalents and the polyphosphoric acid is employed in an amount in the range of from about 2 to about 4 equivalents per equivalent of ketoamide I.
Step A is suitably conducted at a temperature in the range of from about 0 to about 80xc2x0 C. and is typically conducted at a temperature in the range of from about 25 to about 60xc2x0 C. (e.g., from about 30 to about 50xc2x0 C.).
In a suitable procedure for conducting Step A, liquid oleum is charged to the reaction vessel and cooled (e.g., to a temperature in the range of from about 5 to about 15xc2x0 C.), after which polyphosphoric acid is slowly poured into the cooled oleum, followed by addition of ketoamide I while keeping the mixture cool (e.g., below about 25xc2x0 C.). Upon completion of the ketoamide I addition, the mixture is heated to and maintained at a suitable reaction temperature until the reaction is complete or, alternatively, a desired amount of conversion is achieved. The reaction can be quenched by addition of water. The piperazine II can be recovered by conventional techniques, such as, for example, by adding an organic solvent to form an organic phase containing piperazine II and an aqueous phase, separating the phases, and recovering piperazine II from the organic phase (e.g., by concentrating and/or cooling the solution to precipitate piperazine II).
In still another aspect of Step A, the ketoamide I is employed as the sulfate salt (e.g., the bis-sulfate salt). The addition of the sulfate salt to the oleum has been found to be less exothermic than the addition of the corresponding free base. The use of the sulfate salt has also been found to avoid or minimize the formation of gummy solids that have been observed with the free base.
The ketoamide I reactant employed in Step A can be prepared, for example, by Scheme C as follows, wherein a, R1, R2, R3, and R6 are each as originally defined above with respect to process of the invention comprising Step A or as set forth in any of the foregoing embodiments or aspects of Step A: 
The present invention includes a process for preparing a Boc aminoketone of formula C4 which comprises:
deprotonating Weinreb amide C3 by treatment with a Grignard of formula (C1-C4 alkyl)MgX wherein X is Cl or Br; and
reacting the deprotonated Weinreb amide with Grignard C2 of formula R1xe2x80x94MgX to obtain the Boc aminoketone C4.
In this process, R1 in C2 and C4 is as originally defined above or as defined in any of the embodiments or aspects set forth for Step A. Both steps of this process are conducted in inert solvents such as dialkyl ethers (e.g., ethyl ether) and cyclic ethers and diethers (e.g., THF). In one embodiment, from about 0.9 to about 1.1 equivalents of (C1-C4 alkyl)MgX is employed per equivalent of C3 and from about 0.9 to about 1.1 equivalents of R1xe2x80x94MgX is employed per equivalent of C3. The deprotonation step is typically conducted at a relatively low temperature; e.g., from about xe2x88x9210 to about 15xc2x0 C. The reaction of the deprotonated Weinreb amide with R1xe2x80x94MgX is typically conducted by adding R1xe2x80x94MgX to the deprotonated Weinreb amide at a low temperature (e.g., from about xe2x88x9220 to about 0xc2x0 C.), followed by warming the reaction mixture to a suitable reaction temperature (e.g., from about 20 to about 30xc2x0 C.) and maintaining at reaction temperature until the reaction is complete. As an alternative to this process, the Weinreb amide C3 can be reacted directly with two equivalents of R1xe2x80x94MgX to give C4. Deprotonation of the Weinreb amide prior to reaction with R1xe2x80x94MgX can reduce costs, because the deprotonation can be achieved with one equivalent of a relatively inexpensive (C1-C4 alkyl)MgX such as isopropylMgCl, so that only one equivalent of the typically more expensive R1xe2x80x94MgX is required to obtain C4. The process of the invention has also been found to result in a product C4 with improved purity compared to the product obtained by direct reaction of R1xe2x80x94MgX with C3.
The present invention also includes a process for preparing Compound 16: 
which comprises:
(aa) treating ketoamide 15: 
with fuming sulfuric acid in the presence of polyphosphoric acid to obtain Compound 16.
Embodiments of this process include the process as just described additionally incorporating one or more of the following features:
the fuming sulfuric acid is employed in an amount in the range of from about 5 to about 20 equivalents (or from about 7 to about 11 equivalents) and the polyphosphoric acid is employed in an amount in the range of from about 0.5 to about 10 equivalents (of from about 2 to about 4 equivalents) per equivalent of ketoamide 15;
the ratio of equivalents of fuming sulfuric acid to equivalents of polyphosphoric acid is in the range from about 1:1 to about 30:1 or from about 2:1 to about 4:1;
the acid treatment of ketoamide 15 is conducted at a temperature in the range of from about 0 to about 80xc2x0 C. or from about 25 to about 60xc2x0 C. (e.g., from about 30 to about 50xc2x0 C.); or
the bis-sulfate salt of ketoamide 15 is employed in the process.
The present invention also includes a process for preparing a compound of Formula (IV): 
which comprises:
(A) treating a ketoamide of Formula (I): 
with fuming sulfuric acid in the presence of polyphosphoric acid to obtain a piperazine II: 
(B) reacting the piperazine II with an epoxide of Formula (III): 
xe2x80x83to obtain a compound of Formula (IV); wherein
stereocenter a, G, R1, R2, R3, and R6 are each as originally defined above in the discussion of Step A or as defined in any of the embodiments of Step A set forth above;
A is absent, CH2, CHOH, O, or S;
R7 is C1-C6 alkyl, C1-C6 cycloalkyl, aryl, or heteroaryl; wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents (e.g., from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3 substituents; or is di-substituted; or is mono-substituted) each of which is independently halogen, hydroxy, xe2x80x94C1-C6 haloalkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, or xe2x80x94Oxe2x80x94C1-C6 haloalkyl; and wherein aryl or heteroaryl is optionally substituted with one or more substituents (e.g., from 1 to 5, or from 1 to 4, or from 1 to 3 substituents; or is di-substituted; or is mono-substituted) each of which is independently halogen, hydroxy, xe2x80x94C1-C6 haloalkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 haloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and
R8 and R9 are each independently xe2x80x94H, xe2x80x94C1-C6 alkyl, xe2x80x94C1-C6 haloalkyl, xe2x80x94C1-C6 cycloalkyl, or aryl, wherein the aryl is optionally substituted with one or more substituents (e.g., from 1 to 5, or from 1 to 4, or from 1 to 3 substituents; or is di-substituted; or is mono-substituted) each of which is independently halogen, xe2x80x94OH, xe2x80x94C1-C6 alkyl, xe2x80x94C1-C6 haloalkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, or xe2x80x94Oxe2x80x94C1-C6 haloalkyl; or alternatively
R8 and R9 together with the carbons to which each is attached form a fused benzene ring which is optionally substituted with one or more substituents (e.g., from 1 to 4 or from 1 to 3 substituents; or is di-substituted; or is mono-substituted) each of which is independently halogen, xe2x80x94OH, xe2x80x94C1-C6 alkyl, xe2x80x94C1-C6 haloalkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, or xe2x80x94Oxe2x80x94C1-C6 haloalkyl.
Step A of this process has already been described in detail above. Step B involves the coupling of the epoxide III with the piperazine II with the opening of the epoxide ring to give Compound IV. It is to be understood that any embodiment or aspect of Step A set forth above can be employed with any embodiment or aspect of Step B as described below.
In an embodiment of the process, A in Compounds III and IV is absent, CH2, or O.
In another embodiment of the process, R7 in Compounds III and IV is C1-C6 alkyl, C1-C6 cycloalkyl, phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl, wherein heteroaryl is selected from pyridyl, pyrazinyl, pyrimidinyl, thiophenyl, thiazolyl, pyridofuranyl, pyrimidofuranyl, pyridothienyl, pyridazothienyl, pyridooxazolyl, pyridazooxazolyl, pyrimidooxazolyl, pyridothiazolyl, and pyridazothiazolyl; and wherein substituted phenyl or substituted heteroaryl is substituted with one or more substituents (e.g., substituted with from 1 to 3 substituents, or substituted with 1 or 2 substituents), and each of the substituents on substituted phenyl or substituted heteroaryl is independently halogen, hydroxy, C1-C6 alkyl, C1-C6 fluoroalkyl, or xe2x80x94Oxe2x80x94C1-C6 alkyl.
In another embodiment, R7 in Compounds III and IV is 
each Z is independently hydrogen, halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxy; and
q is an integer from 0 to 2.
In still another embodiment, R7 in Compounds III and IV is 
In still another embodiment, R7 in Compounds III and IV is 
In another embodiment of the process, R8 and R9 are each independently xe2x80x94H, xe2x80x94C1-C4 alkyl, xe2x80x94C1-C4 fluoroalkyl, xe2x80x94C1-C6 cycloalkyl, or phenyl, wherein the phenyl is optionally substituted with one or more substituents (e.g., substituted with from 1 to 3 substituents, or substituted with 1 or 2 substituents) each of which is independently halogen, xe2x80x94C1-C4 alkyl, xe2x80x94C1-C4 fluoroalkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl, or xe2x80x94Oxe2x80x94C1-C4 fluoroalkyl; or alternatively R8 and R9 together with the carbons to which each is attached form a fused benzene ring which is optionally substituted with one or more substituents (e.g., substituted with from 1 to 3 substituents, or substituted with 1 or 2 substituents) each of which is independently halogen, xe2x80x94C1-C4 alkyl, xe2x80x94C1-C4 fluoroalkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl, or xe2x80x94Oxe2x80x94C1-C4 fluoroalkyl.
In another embodiment of the process, R8 and R9 are each independently xe2x80x94H, xe2x80x94C1-C4 alkyl, xe2x80x94C1-C4 fluoroalkyl, or phenyl; or alternatively R8 and R9 together with the carbons to which each is attached form a fused benzene ring which is optionally substituted with one or more substituents (e.g., substituted with from 1 to 3 substituents, or substituted with 1 or 2 substituents) each of which is independently halogen, xe2x80x94C1-C4 alkyl, xe2x80x94C1-C4 fluoroalkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl, or xe2x80x94Oxe2x80x94C1-C4 fluoroalkyl.
In another embodiment of the process, Compound III (and the corresponding moiety in Compound IV) is: 
wherein R7 and R8 are each as originally defined or as defined in any of the preceding embodiments; each Y is independently xe2x80x94H, halogen, xe2x80x94C1-C4 alkyl, xe2x80x94C1-C4 fluoroalkyl, or xe2x80x94Oxe2x80x94C1-C4 alkyl; and p is an integer equal to zero, 1 or 2.
In still another embodiment of the process, Compound III is: 
the corresponding moiety in Compound IV is: 
respectively.
Step B is suitably conducted in a solvent. The solvent employed in the coupling reaction can be any organic compound which under the reaction conditions employed is in the liquid phase, is chemically inert, and will dissolve, suspend, and/or disperse the reactants. Suitable solvents include hydrocarbons, ethers, alcohols, nitrites, and esters. In one embodiment, the solvent is selected from the group consisting of C3-C10 linear and branched alkanes, C1-C10 linear and branched halogenated alkanes, C5-C10 cycloalkanes, C6-C14 aromatic hydrocarbons, dialkyl ethers wherein each alkyl is independently a C1-C6 alkyl, C1-C6 linear and branched alkanes substituted with two xe2x80x94Oxe2x80x94C1-C6 alkyl groups (which are the same or different), C4-C8 cyclic ethers and diethers, C6-C8 aromatic ethers, C1-C6 alkyl esters of C1-C6 alkylcarboxylic acids, C1-C10 alkyl alcohols, C2-C6 aliphatic nitriles, and C7-C10 aromatic nitriles. Exemplary solvents include carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane (DCE), 1,1,2-trichloroethane (TCE), 1,1,2,2-tetrachloroethane, cyclohexane, toluene, o- and m- and p-xylene, ethylbenzene, ethyl ether, MTBE, THF, dioxane, 1,2-dimethoxyethane (DME), anisole, phenetole, methyl acetate, ethyl acetate, ethanol, n- and iso-propanol, tert-butyl alcohol, tert-amyl alcohol, acetonitrile, propionitrile, benzonitrile, and p-tolunitrile.
In another embodiment, the solvent employed in Step B is a C1-C6 alkyl alcohol. In an aspect of this embodiment, the alcohol is methanol, ethanol, isopropanol, t-butyl alcohol, or t-amyl alcohol.
Step B is suitably conducted at a temperature in the range of from about room temperature up to the reflux temperature of the chosen solvent. In one embodiment, the reaction is conducted at a temperature in the range of from about 20 to about 100xc2x0 C. In other embodiments, the temperature is in the range of from about 30 to about 95xc2x0 C., or is in the range of from about 40 to about 95xc2x0 C. (e.g., from about 45 to about 65xc2x0 C.).
Piperazine II and epoxide m can be employed in any proportion which will result in the formation of at least some of Compound IV. Typically, however, the reactants are employed in proportions which will optimize conversion of at least one of the reactants. In one embodiment, the amount of piperazine II employed in Step B is at least about 0.5 equivalent per equivalent of epoxide III, and is typically in the range of from about 1 to about 5 (e.g., from about 1 to about 3) equivalents per equivalent of epoxide III. In another embodiment, piperazine H is employed in an amount of from about 1 to about 2 (e.g., from about 1 to about 1.5) equivalents per equivalent of epoxide III. In an aspect of the preceding embodiment, piperazine II is employed in an amount of from about 1 to about 1.1 equivalents per equivalent of epoxide III.
The solvent, piperazine II, and epoxide III can be charged to the Step B reaction vessel concurrently or sequentially in any order. In a suitable procedure, the piperazine II is dissolved in the chosen solvent, followed by addition of epoxide III. The mixture is then stirred at a suitable reaction temperature until the reaction is complete or, alternatively, until the desired or optimum degree of conversion is obtained.
Product IV can be recovered via conventional techniques, such as by treating a solution of IV with silica gel and/or activated carbon to remove impurities, filtering the solution, concentrating and cooling the filtrate to precipitate IV and separating IV by filtration.
Epoxides of Formula (III) for use in Step B can be prepared via the methods (or routine modifications thereof) described in U.S. Pat. No. 5,728,840.
The present invention also includes a process which comprises Steps A and B as heretofore described, and which further comprises:
(C) treating Compound IV with acid to obtain a compound of Formula (V): 
Step C is an acid deprotection step which affords Compound V, wherein stereocenter a, A, R1, R2, R3, R6, R7, R8, and R9 are as originally defined above in the discussion of Steps A and B or as defined in any of the embodiments of Steps A and B as set forth above. Compounds of Formula (V) are inhibitors of HIV protease, and certain classes of the compounds encompassed by Formula (V) (e.g., those in which R6=fluoroalkyl such as 2,2,2-trifluoroethyl) are inhibitors of mutant forms of HIV protease which are resistant to conventional protease inhibitors such as indinavir. Compounds representative of the classes of compounds of Formula (V) capable of inhibiting mutant protease have exhibited IC50 values below 1 nM against the wild-type enzyme and below 5 nM against the mutant enzymes Q-60, K-60, and V-18 in the assay for inhibition of microbial expressed HIV protease described in International Publication No. WO 01/05230. These compounds have also exhibited CIC95 values below 50 nM against the wild-type viral construct and CIC95 values below 125 nM against the viral constructs Q60, K-60, and V-18 in the cell spread assay described in WO 01/05230. These compounds are generally much more potent in both of these assays than indinavir. Further description of these compounds can be found in WO 01/38332.
In Step C, Compound IV is dissolved in a suitable solvent and brought into contact with the acid. Suitable solvents include polar organic solvents which are chemically inert under the conditions employed in Step C, such as alcohols and ethers. In one embodiment, the solvent is a dialkyl ether wherein each alkyl is independently a C1-C6 alkyl, C1-C6 linear or branched alkane substituted with two xe2x80x94Oxe2x80x94C1-C6 alkyls (which are the same or different), a C4-C8 cyclic ether and diether, or a C1-C6 alkyl alcohol. In an aspect of this embodiment, the solvent is a C1-C6 alkyl alcohol (e.g., methanol).
The acid is suitably a strong acid such as trifluoroacetic acid or HCl. The acid can be introduced directly into a solution of Compound IV (e.g., bubbling gaseous HCl into the solution) or can be charged in the form of a solution, such as an aqueous solution or a solution in suitable organic solvent such as an alcohol (e.g., methanol) or an ether (e.g., THF). The acid treatment is generally conducted at a relatively low temperature (e.g., suitably less than about 20xc2x0 C. and more suitably less than about 10xc2x0 C.). Typically at least about 1 equivalent of acid is employed in Step C per equivalent of Compound IV, and an excess amount of the acid is typically employed. In a suitable procedure, a solution of the acid is added slowly (e.g., dropwise) to a solution of Compound IV while maintaining the solution at a relatively low temperature, in order to avoid a rapid accumulation of heat. Once the reaction is complete or the desired degree of conversion has been obtained, the reaction mixture can be quenched with base and product V recovered by conventional means.
The present invention also includes a process for preparing Compound 25: 
which comprises:
(aa) treating ketoamide 15: 
with fuming sulfuric acid in the presence of polyphosphoric acid to obtain piperazine 16: 
(bb) reacting piperazine 16 with epoxide 24: 
to obtain compound 25.
Embodiments of this process include the process as just described incorporating one or more of the following features:
the fuming sulfuric acid is employed in Step (aa) in an amount in the range of from about 5 to about 20 equivalents (or from about 7 to about 11 equivalents) and the polyphosphoric acid is employed in an amount in the range of from about 0.5 to about 10 equivalents (of from about 2 to about 4 equivalents) per equivalent of ketoamide 15;
the ratio of equivalents of fuming sulfuric acid to equivalents of polyphosphoric acid in Step (aa) is in the range from about 1:1 to about 30:1 or from about 2:1 to about 4:1;
the acid treatment of ketoamide 15 is conducted at a temperature in the range of from about 0 to about 80xc2x0 C. or from about 25 to about 60xc2x0 C. (e.g., from about 30 to about 50xc2x0 C.);
the bis-sulfate salt of ketoamide 15 is employed in Step (aa);
Step (bb) is conducted in a solvent selected from the group consisting of dialkyl ethers wherein each alkyl is independently a C1-C6 alkyl, C1-C6 linear and branched alkanes substituted with two xe2x80x94Oxe2x80x94C1-C6 alkyl groups (which are the same or different), C4-C8 cyclic ethers and diethers, C6-C8 aromatic ethers, C1-C6 alkyl esters of C1-C6 alkylcarboxylic acids, C1-C10 alkyl alcohols, C2-C6 aliphatic nitriles, and C7-C10 aromatic nitriles;
Step (bb) is conducted in a solvent which is a C1-C6 alkyl alcohol;
in Step (bb) piperazine 16 is employed in an amount in the range of from about 1 to about 3 equivalents (e.g., from about 1 to about 1.5 equivalents) per equivalent of Compound 24; or
the reaction in Step (bb) is conducted at a temperature in the range of from about 40 to about 95xc2x0 C. (e.g., from about 45 to about 65xc2x0 C.).
The present invention further includes a process for preparing Compound 26: 
which comprises Steps (aa) and (bb) as set forth above and further comprises:
(cc) treating Compound 25 with acid to obtain Compound 26.
Embodiments of this process include the process as just described incorporating one or more of the following features:
the acid in Step (cc) is an aqueous solution of HCl;
the acid in Step (cc) is a solution of HCl in a C1-C6 alkyl alcohol (e.g., ethanol);
Step (cc) is conducted at a temperature of less than about 10xc2x0 C. (e.g., in the range of from about xe2x88x9210 to about 10xc2x0 C.); or
the acid is employed in an amount of at least about 1 equivalent per equivalent of Compound 25.
Other embodiments of the present invention include the process for preparing Compound 26 via Steps (aa), (bb) and (cc), as originally defined above, additionally incorporating any one or more of the embodiments set forth above for any one or more of Steps (aa), (bb), and (cc).
The present invention also includes a process for enhancing the optical purity of a piperazine of Formula (II): 
which comprises:
(X) forming a solution comprising piperazine II containing a minor portion of undesired optical isomer, 2-naphthalenesulfonic acid, and solvent; and
(Y) crystallizing from the solution a crystalline 2-naphthalenesulfonic acid salt of II having enhanced optical purity;
wherein stereocenter a, R1, R2, R3 and R6 are each as originally defined above in Step A or as defined in any embodiments of Step A set forth above.
A xe2x80x9cminor portionxe2x80x9d in Step X means that undesired optical isomer is present in an amount less than the desired optical isomer. Typically undesired optical isomer is present in an amount of no more than about 15 wt. %, and more typically is present in an amount of less than about 10 wt. %, or even less than about 5 wt. %. Undesired optical isomer includes any isomer(s) of piperazine II which have the undesired configuration at stereocenter a. For example, if the optical purity of piperazine II with stereocenter a in the S configuration is to be enhanced, then the undesired material includes isomer(s) of piperazine II having stereocenter a in the R configuration, irrespective of the occurrence of other chiral centers in the isomer.
The term xe2x80x9cenhanced optical purityxe2x80x9d means that the crystallized 2-naphthalenesulfonic acid (alternatively referred to herein as xe2x80x9c2-NSAxe2x80x9d) salt of II contains a greater proportion of the desired configuration at stereocenter a than the piperazine II starting material.
In an embodiment of this process, R1 in piperaine II is pyridyl which is unsubstituted or substituted with 1 or 2 substituents each of which is independently C1-C4 alkyl or xe2x80x94Oxe2x80x94C1-C4 alkyl; R2 and R3 are either both xe2x80x94H or both methyl; and R6 is C1-C4 alkyl or C1-C4 fluoroalkyl.
The solvent employed in the process can be any organic substance which is chemically inert under the conditions employed in Step X and Step Y and which can dissolve piperazine II and optical isomers thereof and 2-NSA. A suitable class of solvents is the nitriles, including the C2-C6 aliphatic nitriles. A preferred solvent is acetonitrile. In one embodiment, water is employed as a co-solvent with the nitrile solvent. Water co-solvent has been found to promote formation of the solution in Step X. In an aspect of the preceding embodiment, the solvent is acetonitrile and the volume ratio of acetonitrile to water employed in Step X is suitably in the range of from about 1.5:1 to about 10:1, and is typically in the range of from about 2:1 to about 5:1.
In another embodiment of the process, the solvent is acetonitrile and the piperazine II is suitably employed in Step X in an amount in the range of from about 0.01 to about 0.2 grams per mL of acetonitrile, is typically employed in an amount in the range of from about 0.02 to 0.1 g/mL, and is often employed in an amount in the range of from about 0.05 to about 0.07 g/mL.
The 2-NSA can be employed in the process in any proportion with respect to piperazine II which will lead to the formation of a crystalline salt having enhanced optical purity. In one embodiment, the 2-NSA is employed in Step X in an amount in the range of from about 2.5 to about 3.5 equivalents per equivalent of II. In another embodiment, 2-NSA is employed in an amount in the range of from about 2.8 to about 3.0 equivalents per equivalent of II.
In an embodiment of the process, forming the solution in Step X comprises heating a mixture comprising piperazine II containing a minor portion of undesired optical isomer, 2-naphthalenesulfonic acid, and solvent to a temperature sufficient to effect dissolution. In an aspect of this embodiment, the solvent is a nitrile (e.g., acetonitrile), water is employed as a co-solvent, and the mixture is heated to a temperature in the range of from about 30 to about 100xc2x0 C. (e.g., from about 40 to about 80xc2x0 C. or from about 50 to about 60xc2x0 C.). (It is noted that if the reflux temperature of the mixture is below the desired or required dissolution temperature, then a higher than ambient pressure can be applied to achieve the desired temperature.)
Crystallizing the 2-NSA salt of piperazine II in Step Y can be accomplished by cooling, or by concentrating (e.g., by evaporative removal of solvent using heat and/or vacuum), or by both cooling and concentrating (concurrently or sequentially in either order) the solution resulting from Step X. In one embodiment, crystallizing Step Y comprises seeding the solution of Step X with crystalline 2-naphthalenesulfonate salt of II, aging the seeded solution, and then either (i) cooling or concentrating or (ii) cooling and concentrating (concurrently or sequentially in either order) the solution to obtain the crystalline 2-naphthalenesulfonic acid salt of II having enhanced optical purity.
As used herein with respect to a crystallization process, the term xe2x80x9cagingxe2x80x9d and variants thereof (e.g., xe2x80x9cagedxe2x80x9d) mean allowing the components of the solution (e.g., 2-NSA, piperazine H, and the crystal salt thereof) to stay in contact for a time and under conditions effective for completion or optimization of the crystallization. The term xe2x80x9cagingxe2x80x9d and its variants can also refer herein to allowing the reactants of a given reaction to stay in contact for a time and under conditions effective for completion of the reaction. The proper meaning of xe2x80x9cagingxe2x80x9d is clear from the context in which it is used.
Another embodiment of the process comprising Steps X and Y as originally defined above is the process wherein piperazine II is a piperazine of Formula (IIxe2x80x2): 
Any one or more of the embodiments of the process set forth above for piperazine II can be incorporated into this embodiment, and each such incorporation represents an additional aspect of this embodiment.
The present invention further includes a process which comprises Step A as originally defined and described above, which further comprises:
(X) forming a solution comprising the piperazine II product of Step A containing a minor portion of undesired optical isomer, 2-naphthalenesulfonic acid, and solvent; and
(Y) crystallizing from the solution a crystalline 2-naphthalenesulfonic acid salt of II having enhanced optical purity.
Embodiments of this process include the process as just defined incorporating one or more of the embodiments, aspects or features of any one or more of Steps A, X and Y as heretofore described.
The present invention also includes a process for preparing Compound IV which comprises Steps A and B as set forth above and further comprises:
(X) forming a solution comprising the piperazine II product of Step A containing a minor portion of undesired optical isomer, 2-naphthalenesulfonic acid, and solvent; and
(Y) crystallizing from the solution a crystalline 2-naphthalenesulfonic acid salt of II having enhanced optical purity; and
(Z) treating the crystallized salt of II with base (e.g., NaOH) to break the salt and afford Compound II as free base for use in Step B.
Additional embodiments of this process include the process as just described additionally incorporating one or more of the embodiments, aspects, or features of any one or more of Steps A, B, X and Y as defined and described above.
The present invention also includes a process for enhancing the optical purity of Compound 16: 
which comprises:
(xx) forming a solution comprising Compound 16 containing a minor portion of its optical isomer, 2-naphthalenesulfonic acid, acetonitrile, and water;
(yy) crystallizing from the solution a crystalline tris-2-naphthalenesulfonate salt of 16 having enhanced optical purity.
In an embodiment of this process, forming the solution in Step (xx) comprises heating a mixture comprising Compound 16 containing a minor portion of its optical isomer, 2-naphthalenesulfonic acid, acetonitrile, and water to a temperature sufficient to effect dissolution; and crystallizing Step (yy) comprises (i) cooling or concentrating or (ii) cooling and concentrating (concurrently or sequentially in either order) the solution to obtain crystalline tris-2-naphthalenesulfonate salt of 16 with enhanced optical purity. In an aspect of the preceding embodiment, Step (yy) comprises seeding the heated solution of Step (xx) with crystalline tris-naphthalene sulfonate salt of 16, aging the seeded solution at elevated temperature (e.g., a temperature in the range of from about 40 to about 80xc2x0 C.), and then either (i) cooling or concentrating or (ii) cooling and concentrating (concurrently or sequentially in either order) the solution to obtain crystalline tris-2-naphthalenesulfonate salt of 16 with enhanced optical purity.
Additional embodiments of this process include the process as originally described or as described in the preceding embodiment incorporating one or more of the following features:
the volume ratio of acetonitrile to water employed in Step (xx) is in the range of from about 1.5:1 to about 10:1, or from about 2:1 to about 5:1;
Compound 16 is employed in Step (xx) in an amount in the range of from about 0.01 to about 0.2 grams per mL of acetonitrile, or from about 0.05 to about 0.07 g/mL of acetonitrile;
2-naphthalenesulfonic acid is employed in Step (xx) in an amount in the range of from about 2.5 to about 3.5 equivalents per equivalent of 16, or from about 2.8 to about 3.0 equivalents per equivalent of 16; or
the solution in Step (xx) is formed by heating the mixture to a temperature in the range of from about 30 to about 100xc2x0 C., or from about 40 to about 80xc2x0 C., or from about 50 to about 60xc2x0 C.
The present invention also includes a process which comprises Step (aa) as originally defined and described above, which further comprises:
(xx) forming a solution comprising the Compound 16 product of Step (aa) containing a minor portion of its optical isomer, 2-naphthalenesulfonic acid, acetonitrile, and water;
(yy) crystallizing from the solution a crystalline tris-2-naphthalenesulfonate salt of 16 having enhanced optical purity.
Embodiments of this process include the process as just defined incorporating one or more of the embodiments, aspects or features of any one or more of Steps (aa), (xx) and (yy) as heretofore described.
The present invention also includes a 2-naphthalenesulfonic acid salt of a piperazine of Formula IIa or IIb: 
wherein R1, R2, R3, and R6 are each as originally defined above in Step A or as defined in any of the embodiments, aspects or features of Step A as set forth above.
In one embodiment, the salt is a salt of a piperazine of Formula (IIa), wherein
R1 is pyridyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from optionally substituted with C1-C4 alkyl or xe2x80x94Oxe2x80x94C1-C4 alkyl;
R2 and R3 are either both xe2x80x94H or both methyl; and
R6 is C1-C4 alkyl or C1-C4 fluoroalkyl.
In an aspect of the foregoing embodiment, the salt is a tris-(2-naphthalenesulfonic acid) salt of the piperazine of Formula (IIa). In another aspect of the foregoing embodiment, the salt is a tris-(2-naphthalenesulfonic acid) salt of Compound 16: 
The present invention also includes a process for preparing Compound 25 which comprises Steps (aa) and (bb) as set forth above and further comprises:
(xx) forming a solution comprising Compound 16 as obtained from Step (aa) and containing a minor portion of its optical isomer, 2-naphthalenesulfonic acid, acetonitrile, and water;
(yy) crystallizing from the solution a crystalline tris-2-naphthalenesulfonate salt of 16 having enhanced optical purity; and
(zz) treating the crystallized salt of 16 with base (e.g., NaOH) to break the salt and afford Compound 16 as free base for use in Step (bb).
Additional embodiments of this process include the process as just described additionally incorporating one or more of the embodiments, aspects, or features of any one or more of Steps (aa), (bb), (xx), or (yy) as defined and described above.
The present invention also includes a process for purifying 2-naphthalenesulfonic acid, which comprises
(L) heating a mixture comprising crude 2-naphthalenesulfonic acid, acetonitrile, and toluene to a temperature sufficient to dissolve the crude acid and form a system comprising an upper layer containing the major portion of 2-naphthalenesulfonic acid and a lower layer;
(M) separating the upper layer from the lower layer; and
(N) crystallizing purified 2-naphthalenesulfonic acid from the separated upper layer.
The term xe2x80x9ccrude 2-naphthalenesulfonic acidxe2x80x9d refers to 2-NSA which comprises in addition to 2-NSA per se at least one of 1-NSA, sulfuric acid, a naphthalene sulfone, or naphthalene. These impurity components suitably represent a minor amount (i.e., a total of less than 50 wt. %) of the crude 2-NSA, and typically represent less than about 35 wt. % of the crude 2-NSA. Relatively pure 2-NSA (not commercially available) is preferred for use in the processes described above for enhancing the optical purity of piperazine II and piperazine 16. The process comprising Steps L, M and N can provide 2-NSA with a suitable level of purity.
The volume ratio of acetonitrile to toluene in Step L is suitably in the range of from about 1:1 to about 1:8, is typically in the range of from about 1:2 to about 1:6, and is more typically in the range of from about 1:2 to about 1:4.
The amount of crude 2-naphthalenesufonic acid can vary from an amount providing a very dilute to an amount providing a highly concentrated solution. In one embodiment, the crude 2-NSA is suitably present in Step L in an amount in the range of from about 0.1 to about 1 g per mL of acetonitrile. In another embodiment, crude 2-NSA is present in Step L in an amount in the range of from about 0.2 to about 0.8 g per mL of acetonitrile. In still another embodiment, crude 2-NSA is present in an amount in the range of from about 0.4 to about 0.6 g per mL of acetonitrile.
The temperature required in Step L to dissolve the crude acid depends upon the relative proportion of the solvent (acetonitrile and toluene) employed, higher temperatures being required to form a highly concentrated solution. The temperature is suitably in the range of from about 40 to about 100xc2x0 C., and is typically in the range of from about 50 to about 90xc2x0 C. (e.g., from about 70 to about 90xc2x0 C.).
Water can be added to the mixture of Step L in order to promote separation of the layers. Typically no more than about 5 wt. % of water with respect to crude 2-NSA is employed for this purpose, and more typically no more than about 2.5 wt. %
Crystallization in Step N can be achieved by conventional methods such as cooling the solution, or concentrating the solution (e.g., by evaporative removal of solvent using heat and/or vacuum), or cooling and concentrating (concurrently or sequentially in either order) the solution. In one embodiment, crystallizing in Step N comprises seeding the cooled and/or concentrated upper layer with 2-naphthalenesulfonic acid crystals to obtain purified crystalline 2-naphthalenesulfonic acid.
In another embodiment, crystallizing in Step N comprises adding a minor portion of water to the hot top layer, and then (i) cooling or concentrating or (ii) cooling and concentrating (concurrently or sequentially in either order) the layer to form purified crystals of 2-NSA. The amount of water added to the hot top layer is suitably no more than about 10 wt. %, and typically is no more than about 5 wt. % (e.g., from about 1 to about 5 wt. %) of the crude 2-NSA.
In still another embodiment, crystallizing in Step N comprises adding water to the hot top layer and cooling the layer to form an organic upper phase and an aqueous lower phase containing the major portion of 2-naphthalenesulfonic acid, separating and solvent switching the aqueous phase with acetonitrile, adding toluene and heating to form a clear solution, and then (i) cooling or concentrating or (ii) cooling and concentrating (concurrently or sequentially in either order) the switched solution to form purified crystals of 2-naphthalenesulfonic acid. The amount of water added to the hot top layer is suitably at least about 50 wt. %, and typically is at least about 75 wt. % (e.g., from about 75 to about 95 wt. %) of the crude 2-NSA.
If desired, further purification of the crystallized 2-NSA can be achieved by recrystallization of the isolated Step N crystals from acetonitrile.
Still other embodiments of the present invention include any of the processes as originally defined and described above and any embodiments or aspects thereof as heretofore defined, further comprising isolating (which may be alternatively referred to as recovering) the compound of interest from the reaction or crystallization medium (e.g., Compound IV or Compound 25, or piperazine II or piperazine 16).
If desired, the progress of the reaction in any of the above-described chemical reactions can be followed by monitoring the disappearance of a reactant (e.g., piperazine I or epoxide III in Step B) and/or the appearance of the product (e.g., Compound IV in Step B) using TLC, HPLC, NMR or GC.
As used herein, the term xe2x80x9cC1-C6 alkylxe2x80x9d means linear or branched chain alkyl groups having from 1 to 6 carbon atoms and includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. xe2x80x9cC1-C4 alkylxe2x80x9d means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
The term xe2x80x9cxe2x80x94Oxe2x80x94C1-C6 alkylxe2x80x9d refers to an alkoxy group wherein the alkyl is C1 to C6 alkyl as defined above. xe2x80x9cxe2x80x94Oxe2x80x94C1-C4 alkylxe2x80x9d has an analogous meaning; i.e., it is an alkoxy group selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and sec-butoxy.
The term xe2x80x9chalogenxe2x80x9d (which may alternatively be referred to as xe2x80x9chaloxe2x80x9d) refers to fluorine, chlorine, bromine and iodine (alternatively, fluoro, chloro, bromo, and iodo).
The term xe2x80x9cC1-C6 haloalkylxe2x80x9d means a C1 to C6 linear or branched alkyl group as defined above with one or more halogen substituents. The term xe2x80x9cC1-C4 haloalkylxe2x80x9d has an analogous meaning.
The term xe2x80x9cxe2x80x94Oxe2x80x94C1-C6 haloalkylxe2x80x9d means an alkoxy group as defined above with one or more halogen substituents on the alkyl moiety. The term xe2x80x9cxe2x80x94Oxe2x80x94C1-C4 haloalkylxe2x80x9d has an analogous meaning.
The term xe2x80x9cC1-C6 fluoroalkylxe2x80x9d means a C1-C6 alkyl group as defined above with one or more fluorine substituents. The term xe2x80x9cC1-C4 fluoroalkylxe2x80x9d has an analogous meaning. Representative examples of suitable fluoroalkyls include the series (CH2)0-3CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.), 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 3,3,3-trifluoroisopropyl, 1,1,1,3,3,3-hexafluoroisopropyl, and perfluorohexyl:
The term xe2x80x9cxe2x80x94Oxe2x80x94C1-C6 fluoroalkylxe2x80x9d means an xe2x80x94Oxe2x80x94C1-C6 alkyl group as defined above wherein the alkyl moiety has one or more fluorine substituents. The term xe2x80x9cxe2x80x94Oxe2x80x94C1-C4 fluoroalkylxe2x80x9d has an analogous meaning. Representative examples include the series O(CH2)0-3CF3 (i.e., trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoro-n-propoxy, etc.), and 1,1,1,3,3,3-hexafluoroisopropoxy.
The term xe2x80x9cC3-C8 cycloalkylxe2x80x9d refers to a cyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. xe2x80x9cC1-C6 cycloalkylxe2x80x9d has an analogous meaning.
The term xe2x80x9cC3-C6 azacycloalkylxe2x80x9d refers to a saturated cyclic ring containing a ring nitrogen and from 3 to 6 ring carbons. The term includes azetidinyl, pyrrolidinyl, piperidinyl, and hexahydroazepinyl.
The term xe2x80x9carylxe2x80x9d refers herein to phenyl or naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d refers to (i) a 5- or 6-membered aromatic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S, and O or (ii) an 8- to 10-membered bicyclic ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S, and O, wherein at least one of the rings in the bicyclic system is an aromatic ring. The heteroaryl ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure.
The term xe2x80x9csubstitutedxe2x80x9d (e.g., as in xe2x80x9csubstituted heterocyclexe2x80x9d) includes mono- and poly-substitution by a named substituent or substituents to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.
The symbol xe2x80x9cxe2x80x9d in front of an open bond in the structural formula of a group marks the point of attachment of the group to the rest of the molecule.
Combinations of substituents and/or variables are permitted only to the extent such combinations result in chemically stable compounds under the process conditions described herein.
Abbreviations used herein include the following:
ACN=acetonitrile
AIDS=acquired immune deficiency syndrome
Alloc or alloc=allyloxycarbonyl
ARC=AIDS related complex
BOC or Boc=t-butyloxycarbonyl
DMF=dimethylformamide
DSC=differential scanning calorimetry
EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
Et=ethyl
HIV=human immunodeficiency virus
HOBT or HOBt=1-hydroxy benzotriazole hydrate
HPLC=high performance liquid chromatography
IPAc=isopropyl acetate
IPA=isopropyl alcohol
KF=Karl Fisher titration for water
LC=liquid chromatography
LHMDS=lithium hexamethyldisilazide
Me=methyl
MeOH=methanol
MSA=methanesulfonic acid
MTBE=methyl tert-butyl ether
NCS=N-chlorosuccinimide
NMR=nuclear magnetic resonance
NSA=naphthalenesuflonic acid
OTf=triflate
PPA=polyphosphoric acid
i-Pr=isopropyl
TBDC=di t-butyl dicarbonate
TEA=triethylamine
TGA=thermogravimetric analysis
THF=tetrahydrofuran
XRPD=x-ray powder diffraction